Genetic Aspects of Prevention

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Genetic Aspects of Prevention

• Tisha Titus

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Why Genetics??

• Interlaced into many aspects of disease
  treatment
• Rapidly expanding field with broad implications
  for public health and prevention
• IT IS ON THE BOARDS!

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Outline

• Genetics in relation to public health
• Screening as part of genetics
• Genetics and health
• Epigenetics
• Pharmacogenomics pharmacogenetics
• Nutrigenomics nutrigenetics
• Genetics and ethics
• Georgia laws
• Case studies (time permitting)

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Genetics

• Advancing field of medicine and PH
• Resulted in 50 new drugs biological agents
• Insulin
• Erythropoietin
• Nerve growth factor
• Several concerns
• Self-image self confidence
• designer babies
• Eugenics fetal rejection by genome
• Insurability

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Genetic Research Advancement
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Genetic Screening

• Available for hundreds of disorders
• Exciting for prevention
• Worrisome
• Feasibility
• Cost
• Interpretation of results
• Ethical implications
• Effects on insurability
• Genetics associated studies - admixture
• Human Genome Project

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Publically Accepted Screening

• Genes whose effects are attenuated by modifying
  nutrition (DM, high cholesterol)
• Genes whose effects are attenuated by modifying
  environment or lifestyle (allergies, UV light
  sensitivity)
• Genes whose presence is considered a marker for a
  life threatening, but potentially curable disease
  (BRCA 12)
• Genes whose presence affects whether treatment
  with a specific drug is likely to be effective
  (estrogen receptors)

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What Screening Offers

• Finding genetic abnormalities
• Single gene abnormalities (PKU)
• Multiple gene interactions (DM, obesity)
• Improving treatment options
• Drug susceptibility (Cytochrome P450)
• Identifies tolerance to environmental and
  occupational exposures
• Protection of hemoglobinopathies (Sickle cell)
• Metabolic protection (Native Americans)
• Points of intervention

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Screening and Intervention
Intervention
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Screening and Management
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Epigenetics Primer

• The study of heritable changes in genome function
  that occur without a change in DNA sequence
• Gene methylation (Cytosine DNA)
• Histone acetylation / deacetlyation
• Genomic imprinting
• X-chromosome dosage compensation (random
  inactivation)

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Epigenetic Effects

• All calico cats are female
• Random X inactivation
• Nucleus replacement
• Development reactivates
• both X chromosomes and
• then randomly inactivates
• No two calico clones will
• have the same coloring
• pattern

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Epigenetics Effects

• Exposure to
• Biphenol A changes
• the expression of
• coat colors
• Agouti methylation
• BPA exposure
• hinders methylation
• and lightens coat
• color
• Agouti associated
• with yellow coat
• obesity

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Epigenetics Effects

• Angelman Syndrome

• Prader Willi Syndrome

• Dual paternal copies
• Mental retardation
• Speech problems
• Stiff arm movements
• Stiff, uncoordinated walk
• Seizures
• Laughter outbursts

• Dual maternal copies
• Poor muscle tone
• Weak cry
• Food obsession/ uncontrollable appetite leading
  to obesity
• Mentally retarded
• Short stature

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Pharmacology Genetics

• Pharmacogenetics

• Pharmacogenomics

• The study of inherited difference/variation in
  drug metabolism and response

• The general study of all of the different genes
  that determine drug behavior

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Pharmacogenomics/genetics Primer

• Examines the inherited variations in genes that
  dictate drug response (efficacy toxicity)
• Explores the ways these variations can be used to
  predict whether a patient will have a good
  response, bad response or no response to a drug

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Pharmacogenomics/genetics Benefits

• More powerful medicines
• Better, safer drugs the first time
• More accurate methods of determining appropriate
  drug dosages
• Advanced screening for disease
• Better vaccines
• Improvements in drug discovery and approval
  process
• Decrease in the overall cost of heathcare

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Pharmacogenomics/genetics Barriers

• Complexity of finding gene variations that affect
  drug response
• Limited drug alternatives
• Disincentives for drug companies to make multiple
  pharmacogenomic products
• Educating health care providers

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Pharmacogenomics/genetics Examples

• Fast slow acetylators of suxamethonium cholride
  with varied recovery effects from anesthesia
• TPMT and bone marrow supression (those with
  variant alleles need 1/10 of usual dose)
• Cytochrome P450 metabolism (ultra-rapid, rapid,
  indeterminate and slow metabolizers)
• CYP 2D6 variants and Tamoxifen response

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Nutrition Genetics

• Nutrigenetics

• Nutrigenomics

• Examine the effect of genetic variation on the
  interaction between diet and disease or on
  nutrient requirements
• Looks at the role of genes in determining the
  response to nutrients

• To study the effects of genetic variation on the
  interaction between diet and disease
• Looks at the role of nutrients in gene expression

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Nutrigenomics/genetics Primer

• Aims
• To study the genome-wide influences of nutrition
• Identify genes that influence the risk of diet
  related diseases
• To understand the mechanisms that underlie
  genetic predisposition
• Nutrients are dietary signals detected by
  cellular sensor systems that influence
  gene/protein expression metabolite production
  (via transcription factors)

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Nutrigenomics/genetics Tenets

1. Improper diets are risk factors for disease
2. Dietary chemicals alter gene expression and/or
   genome structure
3. Influence of diet on health depends upon an
   individuals genetic make-up
4. Genes regulated by diet play a role in chronic
   disease
5. Individualized nutrition (diets based on
   genotype, nutritional requirements and status)
   prevent mitigate chronic disease

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Nutrigenomics/genetics Barriers

• Food is complex
• Most nutrients are weak dietary signals must be
  considered in the context of chronic exposure
• Need to demonstrate measurement of weak dietary
  signals or detection of nutrient deficiency
• Understanding polygenetic diet related disease
• Preparation for genome-scale questions
• Cost

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Nutrigenomics/genetics Challenges

• Identify nutrient influenced molecular pathways
• Determine the down-stream effects of specific
  nutrients
• Identify specific polymorphisms that are linked
  to altered risk of disease or sensitivity to diet

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Nutrigenomics/genetics Examples

• Alcohol effects on LDL based on ApoE genotype
• ApoE4 elevated LDL with moderate alcohol intake
• ApoE2 effects reversed (generally protective)
• MTHFR and vascular health
• MTHFR allele carriers with relative folate
  deficiency develop high homocysteine (independent
  CV risk factor negative indicator of vascular
  health)
• Salt sensitivity (50) with hypertension

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Genetics and Ethics

• Who owns genes (commercialization)
• For profit screening
• Cost of screening and intervention
• Patient rights / privacy / confidentiality
• Right to results / fairness of information use
• Insurance disputes
• Psychological impact / stigmatization
• Reproductive decision making
• Interpretation uncertainties

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Georgia Genetics Laws

• No legislation for
• Licensure of genetic counselors
• Genetic employment laws
• Cloning laws
• Life, disability or long-term care insurance
• Stem cell research
• We do have
• Genetic privacy laws
• State antidiscrimination laws (insurance)
• Newborn screening

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Georgia Genetic Laws Cont

• Genetic Privacy
• Consent for genetic testing
• Consent for genetic information disclosure
• Genetic information defined as personal property
• Specific penalties for genetic privacy violations

• Antidiscrimination
• Cant establish rules of eligibility based on
  genetic information
• Cant require genetic tests/information
• Cant use genetic information for risk selection
  and/or classification
• Cant disclose information without consent

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Take Home

• Genetics is becoming increasingly more important
  for public health and prevention
• Currently limited in scope
• Clouded in controversy
• Many anticipated changes ahead
• Policy guiding research
• Research application to public private
  practices (including funding)
• Confidentiality
• Equity of care